JP2011520898A5 - - Google Patents

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JP2011520898A5
JP2011520898A5 JP2011509636A JP2011509636A JP2011520898A5 JP 2011520898 A5 JP2011520898 A5 JP 2011520898A5 JP 2011509636 A JP2011509636 A JP 2011509636A JP 2011509636 A JP2011509636 A JP 2011509636A JP 2011520898 A5 JP2011520898 A5 JP 2011520898A5
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amino acid
antibody
acid sequence
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Priority claimed from PCT/US2009/043734 external-priority patent/WO2009140348A2/en
Publication of JP2011520898A publication Critical patent/JP2011520898A/en
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当業者の知る通り、本発明の抗体は種々の用途を有する。例えば本発明の蛋白質は例えば敗血症、癌（例えば多発性骨髄腫疾患（ＭＭ）、腎細胞癌（ＲＣＣ）、形質細胞性白血病、リンパ腫、Ｂ−リンパ増殖性障害（ＢＬＰＤ）、および前立腺癌）、骨再吸収、骨粗鬆症、悪液質、乾癬、メサンギウム増殖性糸球体腎炎、カポジ肉腫、ＡＩＤＳ関連リンパ腫、および炎症性疾患（例えば、関節リウマチ、全身発症性若年性特発性関節炎、高ガンマグロブリン血症、クローン病、潰瘍性結腸炎、全身性エリテマトーデス（ＳＬＥ）、多発性硬化症、キャッスルマン病、ＩｇＭ免疫グロブリン血症、心臓粘液腫、喘息、アレルギー性喘息および自己免疫インシュリン依存性真正糖尿病）のような障害におけるＩＬ−６受容体活性化を防止するための治療剤として使用される。本発明の抗体はまた、診断キット中の試薬として、または診断ツールとして使用され、あるいはこれらの抗体は治療用試薬を生成するための競合試験において使用できる。
本発明は、例えば以下の項目を提供する。
（項目１）
単離された完全ヒト抗体であって、ｇｐ１３０媒介細胞内シグナリングカスケードが該抗体の存在下で活性化されないように、ＩＬ−６／ＩＬ−６Ｒ複合体（ＩＬ−６Ｒｃ）に結合し、そしてＩＬ−６／ＩＬ−６Ｒ受容体複合体（ＩＬ−６Ｒｃ）がｇｐ１３０に結合することを防止し、ここで該抗体が：
（ｉ）下記：
（ａ）軽鎖相補性決定領域３（ＣＤＲ３）におけるアミノ酸配列ＱＱＳＸＳＹＰＬＴ（ここで、ＸはＮまたはＱである）；
（ｂ）重鎖相補性決定領域２（ＣＤＲ２）におけるアミノ酸配列ＧＩＩＰＸ １ ＦＸ ２ ＴＴＫＹＡＱＸ ３ ＦＱＧ（ここで、Ｘ １ はＬまたはＡであり、Ｘ ２ はＤまたはＥであり、そしてＸ ３ はＱまたはＫである）；
（ｃ）重鎖相補性決定領域３（ＣＤＲ３）におけるアミノ酸配列ＤＲＤＩＬＴＤＹＹＰＸＧＧＭＤＶ（ここで、ＸはＭまたはＬである）；および、
（ｄ）フレームワーク領域３（ＦＲＷ３）におけるアミノ酸配列ＴＡＶＸＹＣＡＲ（ここで、ＸはＦまたはＹである）；
を含む抗体；
（ｉｉ）配列番号２のアミノ酸配列を含む可変重鎖領域および配列番号４のアミノ酸配列を含む可変軽鎖領域を含む抗体；
（ｉｉｉ）軽鎖ＣＤＲ３領域におけるアミノ酸配列ＱＱＳＮＳＹＰＬＴ、重鎖ＣＤＲ２領域におけるアミノ酸配列ＧＩＩＰＬＦＤＴＴＫＹＡＱＫＦＱＧ、重鎖ＣＤＲ３領域におけるアミノ酸配列ＤＲＤＩＬＴＤＹＹＰＭＧＧＭＤＶ、およびＦＲＷ３領域におけるアミノ酸配列ＴＡＶＹＹＣＡＲを含む抗体；
（ｉｖ）軽鎖ＣＤＲ３領域におけるアミノ酸配列ＱＱＳＮＳＹＰＬＴ、重鎖ＣＤＲ２領域におけるアミノ酸配列ＧＩＩＰＬＦＤＴＴＫＹＡＱＫＦＱＧ、重鎖ＣＤＲ３領域におけるアミノ酸配列ＤＲＤＩＬＴＤＹＹＰＬＧＧＭＤＶ、およびＦＲＷ３領域におけるアミノ酸配列ＴＡＶＹＹＣＡＲを含む抗体；
（ｖ）軽鎖ＣＤＲ３領域におけるアミノ酸配列ＱＱＳＮＳＹＰＬＴ、重鎖ＣＤＲ２領域におけるアミノ酸配列ＧＩＩＰＡＦＥＴＴＫＹＡＱＫＦＱＧ、重鎖ＣＤＲ３領域におけるアミノ酸配列ＤＲＤＩＬＴＤＹＹＰＬＧＧＭＤＶ、およびＦＲＷ３領域におけるアミノ酸配列ＴＡＶＹＹＣＡＲを含む抗体；ならびに、
（ｖｉ）軽鎖ＣＤＲ３領域におけるアミノ酸配列ＱＱＳＱＳＹＰＬＴ、重鎖ＣＤＲ２領域におけるアミノ酸配列ＧＩＩＰＡＦＥＴＴＫＹＡＱＫＦＱＧ、重鎖ＣＤＲ３領域におけるアミノ酸配列ＤＲＤＩＬＴＤＹＹＰＬＧＧＭＤＶ、およびＦＲＷ３領域におけるアミノ酸配列ＴＡＶＹＹＣＡＲを含む抗体、
よりなる群から選択される抗体を交差ブロッキングする、項目１記載の抗体。
（項目２）
前記抗体がＩＬ−６Ｒｃに対して少なくとも１ｘ１０ −８ の親和性を有する、項目１記載の抗体。
（項目３）
前記抗体がＩＬ−６Ｒｃに対して少なくとも１ｘ１０ −９ の親和性を有する、項目１記載の抗体。
（項目４）
前記抗体がＩＬ−６受容体（ＩＬ−６Ｒ）のドメイン３におけるエピトープに結合し、該エピトープは少なくともアミノ酸配列ＡＥＲＳＫＴを含む、項目１記載の抗体。
（項目５）
前記抗体がＩＬ−６およびＩＬ−６Ｒの間の相互作用をモジュレートしない、項目１記載の抗体。
（項目６）
前記抗体がＩＬ−６Ｒにも結合する、項目１記載の抗体。
（項目７）
前記抗体が配列番号１５のアミノ酸配列を含むＶ Ｈ ＣＤＲ１領域、配列番号１６のアミノ酸配列を含むＶ Ｈ ＣＤＲ２領域、配列番号１７のアミノ酸配列を含むＶ Ｈ ＣＤＲ３領域、配列番号２４のアミノ酸配列を含むＶ Ｌ ＣＤＲ１領域、配列番号２５のアミノ酸配列を含むＶ Ｌ ＣＤＲ２領域、および配列番号２６のアミノ酸配列を含むＶ Ｌ ＣＤＲ３領域を含む、項目１記載の抗体。
（項目８）
前記抗体が：
（ａ）配列番号１５、１８または２１のアミノ酸配列を含むＶ Ｈ ＣＤＲ１領域；
（ｂ）配列番号１６、１９、２２、３３、３４または３５のアミノ酸配列を含むＶ Ｈ ＣＤＲ２領域；
（ｃ）配列番号１７、２０、２３、３６または３７のアミノ酸配列を含むＶ Ｈ ＣＤＲ３領域；
（ｄ）配列番号２４、２７、２８、または３０のアミノ酸配列を含むＶ Ｌ ＣＤＲ１領域；（ｅ）配列番号２５のアミノ酸配列を含むＶ Ｌ ＣＤＲ２領域；および、
（ｆ）配列番号２６、２９、３１または３２のアミノ酸配列を含むＶ Ｌ ＣＤＲ３領域
を含む、項目１記載の単離された抗体。
（項目９）
前記抗体が配列番号２から選択されるアミノ酸配列を含む重鎖可変配列および配列番号４のアミノ酸配列を含む軽鎖可変配列を含む、項目１記載の抗体。
（項目１０）
前記抗体がＩｇＧアイソタイプである、項目１記載の抗体。
（項目１１）
前記抗体がＩｇＧ１アイソタイプである、項目１記載の抗体。
（項目１２）
前記抗体が配列番号２、８、または１２から選択されるアミノ酸配列を含む重鎖可変配列および配列番号４、６、１０または１４のアミノ酸配列を含む軽鎖可変配列を含む、項目１記載の抗体。
（項目１３）
単離された完全ヒトモノクローナル抗ＩＬ−６Ｒｃ抗体、またはそのフラグメントであって、該抗体が：
（ａ）配列番号１５、１８または２１のアミノ酸配列を含むＶ Ｈ ＣＤＲ１領域；
（ｂ）配列番号１６、１９、２２、３３、３４または３５のアミノ酸配列を含むＶ Ｈ ＣＤＲ２領域；
（ｃ）配列番号１７、２０、２３、３６または３７のアミノ酸配列を含むＶ Ｈ ＣＤＲ３領域；
（ｄ）配列番号２４、２７、２８、または３０のアミノ酸配列を含むＶ Ｌ ＣＤＲ１領域；（ｅ）配列番号２５のアミノ酸配列を含むＶ Ｌ ＣＤＲ２領域；および、
（ｆ）配列番号２６、２９、３１または３２のアミノ酸配列を含むＶ Ｌ ＣＤＲ３領域、
を含み、そして、該抗体がＩＬ−６／ＩＬ−６Ｒ複合体に結合する、抗体。
（項目１４）
前記抗体がＩＬ−６Ｒにも結合する、項目１３記載の抗体。
（項目１５）
前記抗体がＩｇＧアイソタイプである、項目１３記載の抗体。
（項目１６）
前記抗体がＩｇＧ１アイソタイプである、項目１３記載の抗体。
（項目１７）
前記抗体が配列番号２、８、または１２から選択されるアミノ酸配列を含む重鎖可変配列および配列番号４、６、１０または１４のアミノ酸配列を含む軽鎖可変配列を含む、項目１３記載の抗体。
（項目１８）
前記抗体が配列番号２から選択されるアミノ酸配列を含む重鎖可変配列および配列番号４のアミノ酸配列を含む軽鎖可変配列を含む、項目１３記載の抗体。
（項目１９）
前記項目のいずれか１項に記載の抗体および担体を含む、医薬組成物。
（項目２０）
対象における関節リウマチ、クローン病、乾癬、多発性硬化症または喘息に関連する臨床適応症の症状を軽減する方法であって、該方法が、項目１〜１８のいずれか一項に記載の抗体を、該軽減を必要とする対象に、関節リウマチ、クローン病、乾癬、多発性硬化症または喘息に関連する臨床適応症の症状を軽減するために十分な量で投与する工程を含む、方法。
（項目２１）
前記対象がヒトである、項目２０記載の方法。
（項目２２）
癌、自己免疫疾患または炎症性障害の症状を軽減する方法であって、該方法が、項目１〜１８のいずれか一項に記載の抗体を、該軽減を必要とする対象に、該対象における癌、自己免疫疾患または炎症性障害の症状を軽減するために十分な量で投与する工程を含む、方法。
（項目２３）
前記対象がヒトである、項目２２記載の方法。
As will be appreciated by those skilled in the art, the antibodies of the present invention have a variety of uses. For example, the proteins of the present invention include, for example, sepsis, cancer (eg, multiple myeloma disease (MM), renal cell carcinoma (RCC), plasma cell leukemia, lymphoma, B-lymphoproliferative disorder (BLPD), and prostate cancer), Bone resorption, osteoporosis, cachexia, psoriasis, mesangial proliferative glomerulonephritis, Kaposi's sarcoma, AIDS-related lymphoma, and inflammatory diseases (eg, rheumatoid arthritis, systemic onset juvenile idiopathic arthritis, hypergammaglobulinemia) , Crohn's disease, ulcerative colitis, systemic lupus erythematosus (SLE), multiple sclerosis, Castleman's disease, IgM immunoglobulinemia, cardiac myxoma, asthma, allergic asthma and autoimmune insulin-dependent diabetes mellitus It is used as a therapeutic agent to prevent IL-6 receptor activation in such disorders. The antibodies of the present invention can also be used as reagents in diagnostic kits or as diagnostic tools, or these antibodies can be used in competitive tests to generate therapeutic reagents.
For example, the present invention provides the following items.
(Item 1)
An isolated fully human antibody that binds to the IL-6 / IL-6R complex (IL-6Rc) such that the gp130-mediated intracellular signaling cascade is not activated in the presence of the antibody, and IL -6 / IL-6R receptor complex (IL-6Rc) is prevented from binding to gp130, wherein the antibody:
(I) The following:
(A) the amino acid sequence QQSXSYPLT in the light chain complementarity determining region 3 (CDR3), wherein X is N or Q;
(B) the amino acid sequence GIPPX 1 FX 2 TTKYAQX 3 FQG in heavy chain complementarity determining region 2 (CDR2) , wherein X 1 is L or A, X 2 is D or E, and X 3 is Q Or K);
(C) the amino acid sequence DRDILTYDYPXGGMDV (where X is M or L) in heavy chain complementarity determining region 3 (CDR3); and
(D) the amino acid sequence TAVXYCAR in framework region 3 (FRW3), where X is F or Y;
An antibody comprising:
(Ii) an antibody comprising a variable heavy chain region comprising the amino acid sequence of SEQ ID NO: 2 and a variable light chain region comprising the amino acid sequence of SEQ ID NO: 4;
(Iii) an antibody comprising the amino acid sequence QQSNSYPLT in the light chain CDR3 region, the amino acid sequence GIIPLFDTTKYAQKFQG in the heavy chain CDR2 region, the amino acid sequence DRDILTDYYPMGGMV in the heavy chain CDR3 region, and the amino acid sequence TAVYYCAR in the FRW3 region;
(Iv) an antibody comprising the amino acid sequence QQSNSYPLT in the light chain CDR3 region, the amino acid sequence GIIPLFDTTKYAQKFQG in the heavy chain CDR2 region, the amino acid sequence DRDILTDYYPLGGMDV in the heavy chain CDR3 region, and the amino acid sequence TAVYYCAR in the FRW3 region;
(V) an antibody comprising the amino acid sequence QQSNSYPLT in the light chain CDR3 region, the amino acid sequence GIIPAFETTKYAQKQQG in the heavy chain CDR2 region, the amino acid sequence DRDILTDYYPLGGMDV in the heavy chain CDR3 region, and the amino acid sequence TAVYYCAR in the FRW3 region;
(Vi) an antibody comprising the amino acid sequence QQSQSYPLT in the light chain CDR3 region, the amino acid sequence GIIPAFETTKYAQKFQG in the heavy chain CDR2 region, the amino acid sequence DRDILTDYYPLGGMDV in the heavy chain CDR3 region, and the amino acid sequence TAVYYCAR in the FRW3 region,
The antibody according to item 1, which cross-blocks an antibody selected from the group consisting of:
(Item 2)
2. The antibody of item 1, wherein the antibody has an affinity of at least 1 × 10 −8 for IL-6Rc .
(Item 3)
2. The antibody of item 1, wherein the antibody has an affinity of at least 1 × 10 −9 for IL-6Rc .
(Item 4)
2. The antibody of item 1, wherein the antibody binds to an epitope in domain 3 of IL-6 receptor (IL-6R), the epitope comprising at least the amino acid sequence AERSKT.
(Item 5)
2. The antibody of item 1, wherein the antibody does not modulate the interaction between IL-6 and IL-6R.
(Item 6)
2. The antibody according to item 1, wherein the antibody also binds to IL-6R.
(Item 7)
The antibody comprises a V H CDR1 region comprising the amino acid sequence of SEQ ID NO: 15, a V H CDR2 region comprising the amino acid sequence of SEQ ID NO: 16, a V H CDR3 region comprising the amino acid sequence of SEQ ID NO: 17, and an amino acid sequence of SEQ ID NO: 24 The antibody according to item 1, comprising a V L CDR1 region, a V L CDR2 region comprising the amino acid sequence of SEQ ID NO: 25 , and a V L CDR3 region comprising the amino acid sequence of SEQ ID NO: 26 .
(Item 8)
The antibody is:
(A) a V H CDR1 region comprising the amino acid sequence of SEQ ID NO: 15, 18 or 21 ;
(B) a V H CDR2 region comprising the amino acid sequence of SEQ ID NO: 16, 19, 22, 33, 34 or 35 ;
(C) a V H CDR3 region comprising the amino acid sequence of SEQ ID NO: 17, 20, 23, 36 or 37 ;
(D) a V L CDR1 region comprising the amino acid sequence of SEQ ID NO: 24, 27, 28, or 30 ; (e) a V L CDR2 region comprising the amino acid sequence of SEQ ID NO: 25 ; and
(F) V L CDR3 region comprising the amino acid sequence of SEQ ID NO: 26, 29, 31 or 32
The isolated antibody of item 1, comprising
(Item 9)
The antibody of item 1, wherein the antibody comprises a heavy chain variable sequence comprising an amino acid sequence selected from SEQ ID NO: 2 and a light chain variable sequence comprising the amino acid sequence of SEQ ID NO: 4.
(Item 10)
2. The antibody according to item 1, wherein the antibody is an IgG isotype.
(Item 11)
The antibody according to item 1, wherein the antibody is an IgG1 isotype.
(Item 12)
The antibody of item 1, wherein the antibody comprises a heavy chain variable sequence comprising an amino acid sequence selected from SEQ ID NO: 2, 8, or 12, and a light chain variable sequence comprising an amino acid sequence of SEQ ID NO: 4, 6, 10 or 14. .
(Item 13)
An isolated fully human monoclonal anti-IL-6Rc antibody, or fragment thereof, wherein the antibody:
(A) a V H CDR1 region comprising the amino acid sequence of SEQ ID NO: 15, 18 or 21 ;
(B) a V H CDR2 region comprising the amino acid sequence of SEQ ID NO: 16, 19, 22, 33, 34 or 35 ;
(C) a V H CDR3 region comprising the amino acid sequence of SEQ ID NO: 17, 20, 23, 36 or 37 ;
(D) a V L CDR1 region comprising the amino acid sequence of SEQ ID NO: 24, 27, 28, or 30 ; (e) a V L CDR2 region comprising the amino acid sequence of SEQ ID NO: 25 ; and
(F) a V L CDR3 region comprising the amino acid sequence of SEQ ID NO: 26, 29, 31 or 32 ,
And the antibody binds to the IL-6 / IL-6R complex.
(Item 14)
14. The antibody according to item 13, wherein the antibody also binds to IL-6R.
(Item 15)
14. The antibody according to item 13, wherein the antibody is an IgG isotype.
(Item 16)
14. The antibody according to item 13, wherein the antibody is an IgG1 isotype.
(Item 17)
14. The antibody of item 13, wherein the antibody comprises a heavy chain variable sequence comprising an amino acid sequence selected from SEQ ID NO: 2, 8, or 12 and a light chain variable sequence comprising an amino acid sequence of SEQ ID NO: 4, 6, 10 or 14. .
(Item 18)
14. The antibody of item 13, wherein the antibody comprises a heavy chain variable sequence comprising an amino acid sequence selected from SEQ ID NO: 2 and a light chain variable sequence comprising the amino acid sequence of SEQ ID NO: 4.
(Item 19)
A pharmaceutical composition comprising the antibody according to any one of the preceding items and a carrier.
(Item 20)
A method for reducing the symptoms of a clinical indication associated with rheumatoid arthritis, Crohn's disease, psoriasis, multiple sclerosis or asthma in a subject, wherein the method comprises the antibody according to any one of items 1-18. Administering to a subject in need thereof in an amount sufficient to reduce symptoms of rheumatoid arthritis, Crohn's disease, psoriasis, multiple sclerosis or clinical indications associated with asthma.
(Item 21)
21. The method of item 20, wherein the subject is a human.
(Item 22)
A method for reducing the symptoms of cancer, autoimmune disease or inflammatory disorder, wherein the method comprises applying the antibody according to any one of items 1 to 18 to a subject in need of the reduction in the subject. Administering a sufficient amount to alleviate symptoms of cancer, autoimmune disease or inflammatory disorder.
(Item 23)
24. The method of item 22, wherein the subject is a human.

Claims (23)

単離された完全ヒト抗体であって、ｇｐ１３０媒介細胞内シグナリングカスケードが該抗体の存在下で活性化されないように、ＩＬ−６／ＩＬ−６Ｒ複合体（ＩＬ−６Ｒｃ）に結合し、そしてＩＬ−６／ＩＬ−６Ｒ受容体複合体（ＩＬ−６Ｒｃ）がｇｐ１３０に結合することを防止し、ここで該抗体が：
（ｉ）下記：
（ａ）軽鎖相補性決定領域３（ＣＤＲ３）におけるアミノ酸配列ＱＱＳＸＳＹＰＬＴ（ここで、ＸはＮまたはＱである）；
（ｂ）重鎖相補性決定領域２（ＣＤＲ２）におけるアミノ酸配列ＧＩＩＰＸ１ＦＸ２ＴＴＫＹＡＱＸ３ＦＱＧ（ここで、Ｘ１はＬまたはＡであり、Ｘ２はＤまたはＥであり、そしてＸ３はＱまたはＫである）；
（ｃ）重鎖相補性決定領域３（ＣＤＲ３）におけるアミノ酸配列ＤＲＤＩＬＴＤＹＹＰＸＧＧＭＤＶ（ここで、ＸはＭまたはＬである）；および、
（ｄ）フレームワーク領域３（ＦＲＷ３）におけるアミノ酸配列ＴＡＶＸＹＣＡＲ（ここで、ＸはＦまたはＹである）；
を含む抗体；
（ｉｉ）配列番号２のアミノ酸配列を含む可変重鎖領域および配列番号４のアミノ酸配列を含む可変軽鎖領域を含む抗体；
（ｉｉｉ）軽鎖ＣＤＲ３領域におけるアミノ酸配列ＱＱＳＮＳＹＰＬＴ、重鎖ＣＤＲ２領域におけるアミノ酸配列ＧＩＩＰＬＦＤＴＴＫＹＡＱＫＦＱＧ、重鎖ＣＤＲ３領域におけるアミノ酸配列ＤＲＤＩＬＴＤＹＹＰＭＧＧＭＤＶ、およびＦＲＷ３領域におけるアミノ酸配列ＴＡＶＹＹＣＡＲを含む抗体；
（ｉｖ）軽鎖ＣＤＲ３領域におけるアミノ酸配列ＱＱＳＮＳＹＰＬＴ、重鎖ＣＤＲ２領域におけるアミノ酸配列ＧＩＩＰＬＦＤＴＴＫＹＡＱＫＦＱＧ、重鎖ＣＤＲ３領域におけるアミノ酸配列ＤＲＤＩＬＴＤＹＹＰＬＧＧＭＤＶ、およびＦＲＷ３領域におけるアミノ酸配列ＴＡＶＹＹＣＡＲを含む抗体；
（ｖ）軽鎖ＣＤＲ３領域におけるアミノ酸配列ＱＱＳＮＳＹＰＬＴ、重鎖ＣＤＲ２領域におけるアミノ酸配列ＧＩＩＰＡＦＥＴＴＫＹＡＱＫＦＱＧ、重鎖ＣＤＲ３領域におけるアミノ酸配列ＤＲＤＩＬＴＤＹＹＰＬＧＧＭＤＶ、およびＦＲＷ３領域におけるアミノ酸配列ＴＡＶＹＹＣＡＲを含む抗体；ならびに、
（ｖｉ）軽鎖ＣＤＲ３領域におけるアミノ酸配列ＱＱＳＱＳＹＰＬＴ、重鎖ＣＤＲ２領域におけるアミノ酸配列ＧＩＩＰＡＦＥＴＴＫＹＡＱＫＦＱＧ、重鎖ＣＤＲ３領域におけるアミノ酸配列ＤＲＤＩＬＴＤＹＹＰＬＧＧＭＤＶ、およびＦＲＷ３領域におけるアミノ酸配列ＴＡＶＹＹＣＡＲを含む抗体、
よりなる群から選択される抗体を交差ブロッキングする、抗体。 An isolated fully human antibody that binds to the IL-6 / IL-6R complex (IL-6Rc) such that the gp130-mediated intracellular signaling cascade is not activated in the presence of the antibody, and IL -6 / IL-6R receptor complex (IL-6Rc) is prevented from binding to gp130, wherein the antibody:
(I) The following:
(A) the amino acid sequence QQSXSYPLT in the light chain complementarity determining region 3 (CDR3), wherein X is N or Q;
(B) the amino acid sequence GIPPX 1 FX 2 TTKYAQX 3 FQG in heavy chain complementarity determining region 2 (CDR2), wherein X 1 is L or A, X 2 is D or E, and X 3 is Q Or K);
(C) the amino acid sequence DRDILTYDYPXGGMDV (where X is M or L) in heavy chain complementarity determining region 3 (CDR3); and
(D) the amino acid sequence TAVXYCAR in framework region 3 (FRW3), where X is F or Y;
An antibody comprising:
(Ii) an antibody comprising a variable heavy chain region comprising the amino acid sequence of SEQ ID NO: 2 and a variable light chain region comprising the amino acid sequence of SEQ ID NO: 4;
(Iii) an antibody comprising the amino acid sequence QQSNSYPLT in the light chain CDR3 region, the amino acid sequence GIIPLFDTTKYAQKFQG in the heavy chain CDR2 region, the amino acid sequence DRDILTDYYPMGGMV in the heavy chain CDR3 region, and the amino acid sequence TAVYYCAR in the FRW3 region;
(Iv) an antibody comprising the amino acid sequence QQSNSYPLT in the light chain CDR3 region, the amino acid sequence GIIPLFDTTKYAQKFQG in the heavy chain CDR2 region, the amino acid sequence DRDILTDYYPLGGMDV in the heavy chain CDR3 region, and the amino acid sequence TAVYYCAR in the FRW3 region;
(V) an antibody comprising the amino acid sequence QQSNSYPLT in the light chain CDR3 region, the amino acid sequence GIIPAFETTKYAQKQQG in the heavy chain CDR2 region, the amino acid sequence DRDILTDYYPLGGMDV in the heavy chain CDR3 region, and the amino acid sequence TAVYYCAR in the FRW3 region;
(Vi) an antibody comprising the amino acid sequence QQSQSYPLT in the light chain CDR3 region, the amino acid sequence GIIPAFETTKYAQKFQG in the heavy chain CDR2 region, the amino acid sequence DRDILTDYYPLGGMDV in the heavy chain CDR3 region, and the amino acid sequence TAVYYCAR in the FRW3 region,
Cross-blocking antibodies are selected from the group consisting of, antibody. 前記抗体がＩＬ−６Ｒｃに対して少なくとも１ｘ１０−８の親和性を有する、請求項１記載の抗体。 The antibody of claim 1, wherein the antibody has an affinity of at least 1 × 10 −8 for IL-6Rc. 前記抗体がＩＬ−６Ｒｃに対して少なくとも１ｘ１０−９の親和性を有する、請求項１記載の抗体。 The antibody of claim 1, wherein the antibody has an affinity of at least 1 × 10 −9 for IL-6Rc. 前記抗体がＩＬ−６受容体（ＩＬ−６Ｒ）のドメイン３におけるエピトープに結合し、該エピトープは少なくともアミノ酸配列ＡＥＲＳＫＴを含む、請求項１記載の抗体。 2. The antibody of claim 1, wherein the antibody binds to an epitope in domain 3 of the IL-6 receptor (IL-6R), the epitope comprising at least the amino acid sequence AERSKT. 前記抗体がＩＬ−６およびＩＬ−６Ｒの間の相互作用をモジュレートしない、請求項１記載の抗体。 2. The antibody of claim 1, wherein the antibody does not modulate the interaction between IL-6 and IL-6R. 前記抗体がＩＬ−６Ｒにも結合する、請求項１記載の抗体。 2. The antibody of claim 1, wherein the antibody also binds to IL-6R. 前記抗体が配列番号１５のアミノ酸配列を含むＶＨＣＤＲ１領域、配列番号１６のアミノ酸配列を含むＶＨＣＤＲ２領域、配列番号１７のアミノ酸配列を含むＶＨＣＤＲ３領域、配列番号２４のアミノ酸配列を含むＶＬＣＤＲ１領域、配列番号２５のアミノ酸配列を含むＶＬＣＤＲ２領域、および配列番号２６のアミノ酸配列を含むＶＬＣＤＲ３領域を含む、請求項１記載の抗体。 The antibody comprises a V H CDR1 region comprising the amino acid sequence of SEQ ID NO: 15, a V H CDR2 region comprising the amino acid sequence of SEQ ID NO: 16, a V H CDR3 region comprising the amino acid sequence of SEQ ID NO: 17, and an amino acid sequence of SEQ ID NO: 24 2. The antibody of claim 1, comprising a V L CDR1 region, a V L CDR2 region comprising the amino acid sequence of SEQ ID NO: 25, and a V L CDR3 region comprising the amino acid sequence of SEQ ID NO: 26. 前記抗体が：
（ａ）配列番号１５、１８または２１のアミノ酸配列を含むＶＨＣＤＲ１領域；
（ｂ）配列番号１６、１９、２２、３３、３４または３５のアミノ酸配列を含むＶＨＣＤＲ２領域；
（ｃ）配列番号１７、２０、２３、３６または３７のアミノ酸配列を含むＶＨＣＤＲ３領域；
（ｄ）配列番号２４、２７、２８、または３０のアミノ酸配列を含むＶＬＣＤＲ１領域；（ｅ）配列番号２５のアミノ酸配列を含むＶＬＣＤＲ２領域；および、
（ｆ）配列番号２６、２９、３１または３２のアミノ酸配列を含むＶＬＣＤＲ３領域
を含む、請求項１記載の単離された抗体。 The antibody is:
(A) a V H CDR1 region comprising the amino acid sequence of SEQ ID NO: 15, 18 or 21;
(B) a V H CDR2 region comprising the amino acid sequence of SEQ ID NO: 16, 19, 22, 33, 34 or 35;
(C) a V H CDR3 region comprising the amino acid sequence of SEQ ID NO: 17, 20, 23, 36 or 37;
(D) a V L CDR1 region comprising the amino acid sequence of SEQ ID NO: 24, 27, 28, or 30; (e) a V L CDR2 region comprising the amino acid sequence of SEQ ID NO: 25; and
(F) The isolated antibody of claim 1, comprising a V L CDR3 region comprising the amino acid sequence of SEQ ID NO: 26, 29, 31 or 32. 前記抗体が配列番号２から選択されるアミノ酸配列を含む重鎖可変配列および配列番号４のアミノ酸配列を含む軽鎖可変配列を含む、請求項１記載の抗体。 2. The antibody of claim 1, wherein the antibody comprises a heavy chain variable sequence comprising an amino acid sequence selected from SEQ ID NO: 2 and a light chain variable sequence comprising the amino acid sequence of SEQ ID NO: 4. 前記抗体がＩｇＧアイソタイプである、請求項１記載の抗体。 2. The antibody of claim 1, wherein the antibody is an IgG isotype. 前記抗体がＩｇＧ１アイソタイプである、請求項１記載の抗体。 The antibody of claim 1, wherein the antibody is an IgG1 isotype. 前記抗体が配列番号２、８、または１２から選択されるアミノ酸配列を含む重鎖可変配列および配列番号４、６、１０または１４のアミノ酸配列を含む軽鎖可変配列を含む、請求項１記載の抗体。 2. The antibody of claim 1, wherein the antibody comprises a heavy chain variable sequence comprising an amino acid sequence selected from SEQ ID NO: 2, 8, or 12 and a light chain variable sequence comprising an amino acid sequence of SEQ ID NO: 4, 6, 10 or 14. antibody. 単離された完全ヒトモノクローナル抗ＩＬ−６Ｒｃ抗体、またはそのフラグメントであって、該抗体が：
（ａ）配列番号１５、１８または２１のアミノ酸配列を含むＶＨＣＤＲ１領域；
（ｂ）配列番号１６、１９、２２、３３、３４または３５のアミノ酸配列を含むＶＨＣＤＲ２領域；
（ｃ）配列番号１７、２０、２３、３６または３７のアミノ酸配列を含むＶＨＣＤＲ３領域；
（ｄ）配列番号２４、２７、２８、または３０のアミノ酸配列を含むＶＬＣＤＲ１領域；（ｅ）配列番号２５のアミノ酸配列を含むＶＬＣＤＲ２領域；および、
（ｆ）配列番号２６、２９、３１または３２のアミノ酸配列を含むＶＬＣＤＲ３領域、
を含み、そして、該抗体がＩＬ−６／ＩＬ−６Ｒ複合体に結合する、抗体。 An isolated fully human monoclonal anti-IL-6Rc antibody, or fragment thereof, wherein the antibody:
(A) a V H CDR1 region comprising the amino acid sequence of SEQ ID NO: 15, 18 or 21;
(B) a V H CDR2 region comprising the amino acid sequence of SEQ ID NO: 16, 19, 22, 33, 34 or 35;
(C) a V H CDR3 region comprising the amino acid sequence of SEQ ID NO: 17, 20, 23, 36 or 37;
(D) a V L CDR1 region comprising the amino acid sequence of SEQ ID NO: 24, 27, 28, or 30; (e) a V L CDR2 region comprising the amino acid sequence of SEQ ID NO: 25; and
(F) a V L CDR3 region comprising the amino acid sequence of SEQ ID NO: 26, 29, 31 or 32,
And the antibody binds to the IL-6 / IL-6R complex. 前記抗体がＩＬ−６Ｒにも結合する、請求項１３記載の抗体。 14. The antibody of claim 13, wherein the antibody also binds to IL-6R. 前記抗体がＩｇＧアイソタイプである、請求項１３記載の抗体。 14. The antibody of claim 13, wherein the antibody is an IgG isotype. 前記抗体がＩｇＧ１アイソタイプである、請求項１３記載の抗体。 14. The antibody of claim 13, wherein the antibody is an IgG1 isotype. 前記抗体が配列番号２、８、または１２から選択されるアミノ酸配列を含む重鎖可変配列および配列番号４、６、１０または１４のアミノ酸配列を含む軽鎖可変配列を含む、請求項１３記載の抗体。 14. The antibody of claim 13, wherein the antibody comprises a heavy chain variable sequence comprising an amino acid sequence selected from SEQ ID NO: 2, 8, or 12 and a light chain variable sequence comprising an amino acid sequence of SEQ ID NO: 4, 6, 10 or 14. antibody. 前記抗体が配列番号２から選択されるアミノ酸配列を含む重鎖可変配列および配列番号４のアミノ酸配列を含む軽鎖可変配列を含む、請求項１３記載の抗体。 14. The antibody of claim 13, wherein the antibody comprises a heavy chain variable sequence comprising an amino acid sequence selected from SEQ ID NO: 2 and a light chain variable sequence comprising the amino acid sequence of SEQ ID NO: 4. 請求項１〜１８のいずれか１項に記載の抗体および担体を含む、医薬組成物。 In any one of the 請 Motomeko 1-18 comprising the antibody and a carrier, wherein the pharmaceutical composition. 対象における関節リウマチ、クローン病、乾癬、多発性硬化症または喘息に関連する臨床適応症の症状を軽減するための組成物であって、該組成物は、請求項１〜１８のいずれか一項に記載の抗体を、関節リウマチ、クローン病、乾癬、多発性硬化症または喘息に関連する該臨床適応症の該症状を軽減するために十分な量で含み、そして該組成物は、該軽減を必要とする対象に投与されることを特徴とする、組成物。 Rheumatoid arthritis, Crohn's disease in a subject, psoriasis, a composition for alleviating the symptoms of clinical indications associated with multiple sclerosis or asthma, the composition is either 請 Motomeko 18 one the antibody according to claim, Takashi Seki arthritis, Crohn's disease, psoriasis, in an amount sufficient to alleviate the symptoms of the clinical indications associated with multiple sclerosis or asthma, and the composition, the A composition characterized in that it is administered to a subject in need of relief . 前記対象がヒトである、請求項２０記載の組成物。 21. The composition of claim 20, wherein the subject is a human. 癌、自己免疫疾患または炎症性障害の症状を軽減するための組成物であって、該組成物は、請求項１〜１８のいずれか一項に記載の抗体を、該対象における癌、自己免疫疾患または炎症性障害の該症状を軽減するために十分な量で含み、そして該組成物は、該軽減を必要とする対象に投与されることを特徴とする、組成物。 A composition for reducing the symptoms of cancer, an autoimmune disease or an inflammatory disorder, wherein the composition comprises the antibody according to any one of claims 1 to 18 and the cancer, autoimmunity in the subject. in an amount sufficient to alleviate the symptoms of the disease or an inflammatory disorder, and wherein the composition is characterized in that it is administered to a subject in need of decreased said light, composition. 前記対象がヒトである、請求項２２記載の組成物。 24. The composition of claim 22, wherein the subject is a human.
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